Does assisted reproductive treatment increase the risk of birth defects in the offspring?
Does assisted reproductive treatment increase the risk of birth defects in the offspring?
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DOI：
10.1111/j.1600-0412.2012.01500.x
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发表时间：
2012-11
影响因子：
4.3
通讯作者：
A. Pinborg;A. Loft;A. Henningsen;S. Ziebe
中科院分区：
文献类型：
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作者：
A. Pinborg;A. Loft;A. Henningsen;S. Ziebe
最近发表在《新英格兰医学杂志》上的一篇论文基于澳大利亚6163例体外受精/卵胞浆内单精子注射（IVF/ICSI）儿童（ICSI后1407例）的队列，Davies等人（1）得出结论，“在多变量调整后，与ICSI相关的出生缺陷风险仍然增加，尽管不能排除残余混杂的可能性”。这引起了很多媒体的关注和对IVF治疗后接受治疗或怀孕的夫妇的担忧。Davies等人提出了一项基于1986年至2002年出生的辅助生殖技术（ART）婴儿队列的优雅研究。然而，这项研究没有参考最近瑞典对2001年至2007年出生的15570名ART婴儿（9372名在ICSI后受孕）进行的基于人群的研究（2）。在澳大利亚的研究中，ART与普通人群相比，出生缺陷的调整后风险总体增加，调整后比值比（aOR 1.28; 95%CI 1.16-1.41）。与普通人群相比，新鲜胚胎IVF的单胎新生儿的校正风险为1.06（95%CI 0.87-1.30），因此显示IVF后出生缺陷的总体风险没有增加。在基于新鲜胚胎移植的ICSI后的单胎新生儿中，该研究显示了调整后的风险增加（aOR 1.55; 95%CI 1.24-1.94）。另一方面，瑞典的研究表明，ICSI与IVF队列（2001-2007）的出生缺陷调整风险的OR为0.90（95%CI 0.78-1.04）。因此，似乎没有任何与IVF方法相关的明显风险差异。与一般人群相比，IVF/ICSI婴儿畸形的aOR为1.15（95%CI 1.07-1.24），与早期发表的老年ART队列（1982-2000年出生的儿童）相比，接受ART的年轻女性队列（2001-2007年）的调整后风险降低（3）。此外，以前与ICSI相关的尿道下裂的风险与普通人群的风险不再有显著差异。最近一项针对ICSI与IVF的荟萃分析得出了与瑞典研究相同的结论，即ICSI没有额外的风险（4）。澳大利亚和瑞典研究之间的一些差异可能解释了关于ICSI的不同发现。澳大利亚研究中所有儿童的随访期为5年，但瑞典研究中的一些儿童的随访期较短。澳大利亚的研究包括20周后因畸形而终止妊娠，而瑞典的研究仅包括20周后的分娩。然而，在IVF和ICSI治疗后的医疗终止中出生缺陷的分布在文章本身或其补充文件中均不可用。此外，澳大利亚的研究还包括那些不是在围产期后获得的脑瘫病例。由于脑瘫与早产密切相关，人们可以质疑将脑瘫定义为出生缺陷是否合适。在澳大利亚的研究中，看到IVF和ICSI儿童之间CP的分布以及出生缺陷的总风险（不包括CP）将是有趣的。到目前为止，关于ART儿童畸形的最大文章以及研究之间的差异应该由Davies等人讨论。应该提到令人欣慰的发现，即年轻或最近的ART人群可能具有较低的畸形风险。这一发现可能是由于生育力低下的父母群体的变化; IVF父母群体在生殖意义上比十年前更健康，即ICSI的适应症更广泛，而不仅仅是非常严重的男性不育症。围产期结局的改善也可能是由于ART刺激方案和实验室技术的改进。此外，澳大利亚的研究包括了瑞典研究中一半多一点的怀孕人数。通过扩大队列，ICSI后观察到的出生缺陷发生率较高的“效应”可能会消失-已知效应与较大的样本量有关，不太容易受到各种方法学方面的混淆，例如纳入或排除标准。早期的研究表明，ICSI儿童携带与男性不育严重程度相关的染色体畸变风险较高（5）;然而，Davies等人没有整理数据以确定澳大利亚数据中是否存在这种情况。
In a recent paper published in the New England Journal of Medicine based on an Australian cohort of 6163 in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) children (1407 after ICSI), Davies et al. (1) conclude that “the risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded”. This has raised a lot of media attention and concerns among couples treated or pregnant after IVF treatment. Davies et al. presented an elegant study based on a cohort of assisted reproductive technologies (ART) infants born from 1986 to 2002. However, the study did not refer to a recent Swedish population-based study on 15 570 ART infants (9372 conceived after ICSI) born between 2001 and 2007 (2). In the Australian study an overall increased adjusted risk of birth defects was demonstrated for ART vs. the general population with an adjusted odds ratio (aOR 1.28; 95%CI 1.16–1.41). Among singleton newborns from fresh-embryo IVF compared with the general population, the adjusted risk was 1.06 (95%CI 0.87–1.30), thus showing no increased overall risk for birth defects after IVF. Among singleton newborns after ICSI based on fresh embryo transfer, the study demonstrated a raised adjusted risk (aOR1.55; 95%CI 1.24–1.94). On the other hand, the Swedish study demonstrated that the adjusted risk of birth defects for the ICSI vs. IVF cohort (2001–2007) had an OR of 0.90 (95%CI 0.78–1.04). Thus there did not seem to be any apparent risk difference associated with the IVF method. The aOR for malformations among IVF/ICSI infants compared with the general population was 1.15 (95%CI 1.07–1.24) and the adjusted risks decreased in the younger cohort of women undergoing ART (2001–2007) compared with the older ART cohort (children born in 1982–2000) published earlier (3). Moreover, the risk of hypospadiasis, which had previously been associated with ICSI, was no longer significantly different from the risk in the general population. A recent meta-analysis looking at ICSI vs. IVF reaches the same conclusion as the Swedish study, i.e. there is no additional risk connected to ICSI (4). Some differences between the Australian and the Swedish study may explain the different findings regarding ICSI. The follow-up period was five years for all children in the Australian study, but shorter for some of the children in the Swedish study. The Australian study included medical termination of pregnancies due to malformations after week 20, whereas the Swedish only included births after week 20. However, the distribution of birth defects in the medical terminations after IVF and ICSI treatments is not available either in the article itself or in its supplementary files. Furthermore, the Australian study also included those cases of cerebral palsy (CP) that were not acquired after the perinatal period. As CP is closely related to preterm birth, one can question whether it is appropriate to define cerebral palsy as a birth defect. It would have been intriguing to see the distribution of CP between IVF and ICSI children and the total risk of birth defects excluding CP in the Australian study. The largest article so far on malformations among ART children and the differences between the studies ought to have been discussed by Davies et al. The reassuring finding that the younger or more recent ART populations may have a lower risk of malformations should have been mentioned. This finding may be due to changes in the subfertile parent populations; the IVF parent populations are healthier in a reproductive sense than a decade ago, i.e. ICSI is performed on broader indications than just very severe male infertility. The improved perinatal outcomes may also be due to improvements in the ART stimulation regimens and laboratory techniques. Moreover, the Australian study included a little more than half the number of pregnancies that were in the Swedish study. By enlarging the cohorts, the “effect” of a higher birth defect incidence observed after ICSI may simply vanish – the known effect related to a larger sample size which is less liable to be confounded by various methodological aspects, such as inclusion or exclusion criteria. Earlier studies have demonstrated that ICSI children carry a higher risk of chromosomal aberrations related to the severity of the male infertility (5); however, Davies et al. do not disentangle data to determine whether this was the case in the Australian figures.